Contributions
Abstract: 135
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Imaging
Objective: To use translocator protein (TSPO) positron emission tomography (PET) to assess microglial activation in white matter lesions in patients with multiple sclerosis (MS).
Methods: 36 MS patients (24 women; aged 22-66; EDSS 1.0-7.0; 7 secondary progressive (SPMS) and 29 relapsing remitting (RRMS)) and 33 healthy volunteers (HV) approximately matched for age (14 women; aged 20-65) underwent a PET scan with a high affinity TSPO ligand ([11C]PBR28 or [18F]PBR111), and 3T MRI (T2 FLAIR and T1). T2 white matter lesions (WML) were segmented on MRI. Peri-lesional volumes were created as sequential 3mm dilatations up to 6 mm from lesion edges. The normal appearing white matter (NAWM) included white matter (WM) without WML and peri-lesional volumes. Low affinity binders for TSPO were excluded from the [11C]PBR28 cohort by genotyping.
TSPO binding was measured as a distribution volume ratio (DVR) with the Logan graphical method, using the caudate as a pseudo-reference region. 6 MS patients underwent repeat [11C]PBR28 PET within 6 weeks. The maximum DVR test-retest variability was < 5%.
Four classes of lesions were distinguished, based on DVR differences of >5% between individual WML, peri-lesional volume and NAWM: DVR in a lesion greater than NAWM (“active lesions”); DVR in lesion and peri-lesional volume less than NAWM (“inactive lesions”); DVR in peri-lesional volume greater than in the lesion and NAWM (“chronic active lesions”) or DVR approximately the same across the three regions (“undifferentiated”).
Results: For both tracers, uptake in NAWM was increased compared with WM of HV. Individual white matter lesions (WML) showed a wide range of DVR. Active lesions were found in all MS patients, including those on different disease modifying treatments. Approximately 50% more inactive lesions were found in patients with SPMS or a disease duration > 16 years, relative to those with RRMS or with a disease duration < 8 years, respectively. There was a correlation between DVR in the WML and EDSS with [18F]PBR111 (Spearman"s ρ=0.69, p=0.027) and a similar trend in the [11C]PBR28 group (ρ=0.37, p=0.073).
Interpretation: For the first time, we have directly evaluated comparable cohorts with two TSPO PET tracers using identical analyses and shown consistent results. A wide heterogeneity of inflammatory activity was found among lesions, consistent with neuropathological studies. Active inflammatory lesions were detected across disease stages and treatments.
Disclosure: G.Datta: nothing to disclose
A.Colasanti: nothing to disclose
N.J. Kalk: nothing to disclose
D.R. Owen: nothing to disclose
G.Scott: nothing to disclose
E.A.Rabiner: holds stock in GSK, has received research funds from AbbVie, and consultancy/speaker fees from GSK, BioTie, Gedeon Richter, Teva and LighlakeTherapeutics
R.N. Gunn: Consultant for GSK, Abbvie, UCB and ITI
A.R. Lingford-Hughes: Research support from GSK
O. Malik: Honoraria and travel bursaries for attendance at conferences from: Biogen Idec, Novartis and Merck/Serono.
O. Ciccarelli: Consultant for Novartis, Biogen and GE
R.Nicholas. Bayer, Biogen, Genzyme, Merck Serono, Roche - honorarium for speaking, advisory boards. Biogen, Genzyme, Novartis - funds for organising education, staff. Biogen, Novartis - Principal investigator.
M. Battaglini: nothing to disclose
N.De Stefano: Honoraria from Schering, Biogen Idec, Teva Pharmaceutical Industries, Novartis, Genzyme, and Merck Serono SA for consulting services, speaking, and travel support. He serves on advisory boards for Biogen Idec, Merck Serono SA, Novartis and Genzyme
This project has been sponsored by Imperial College London, London, UK
Funding has been from GSK and the Wellcome Trust, UK
Abstract: 135
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Imaging
Objective: To use translocator protein (TSPO) positron emission tomography (PET) to assess microglial activation in white matter lesions in patients with multiple sclerosis (MS).
Methods: 36 MS patients (24 women; aged 22-66; EDSS 1.0-7.0; 7 secondary progressive (SPMS) and 29 relapsing remitting (RRMS)) and 33 healthy volunteers (HV) approximately matched for age (14 women; aged 20-65) underwent a PET scan with a high affinity TSPO ligand ([11C]PBR28 or [18F]PBR111), and 3T MRI (T2 FLAIR and T1). T2 white matter lesions (WML) were segmented on MRI. Peri-lesional volumes were created as sequential 3mm dilatations up to 6 mm from lesion edges. The normal appearing white matter (NAWM) included white matter (WM) without WML and peri-lesional volumes. Low affinity binders for TSPO were excluded from the [11C]PBR28 cohort by genotyping.
TSPO binding was measured as a distribution volume ratio (DVR) with the Logan graphical method, using the caudate as a pseudo-reference region. 6 MS patients underwent repeat [11C]PBR28 PET within 6 weeks. The maximum DVR test-retest variability was < 5%.
Four classes of lesions were distinguished, based on DVR differences of >5% between individual WML, peri-lesional volume and NAWM: DVR in a lesion greater than NAWM (“active lesions”); DVR in lesion and peri-lesional volume less than NAWM (“inactive lesions”); DVR in peri-lesional volume greater than in the lesion and NAWM (“chronic active lesions”) or DVR approximately the same across the three regions (“undifferentiated”).
Results: For both tracers, uptake in NAWM was increased compared with WM of HV. Individual white matter lesions (WML) showed a wide range of DVR. Active lesions were found in all MS patients, including those on different disease modifying treatments. Approximately 50% more inactive lesions were found in patients with SPMS or a disease duration > 16 years, relative to those with RRMS or with a disease duration < 8 years, respectively. There was a correlation between DVR in the WML and EDSS with [18F]PBR111 (Spearman"s ρ=0.69, p=0.027) and a similar trend in the [11C]PBR28 group (ρ=0.37, p=0.073).
Interpretation: For the first time, we have directly evaluated comparable cohorts with two TSPO PET tracers using identical analyses and shown consistent results. A wide heterogeneity of inflammatory activity was found among lesions, consistent with neuropathological studies. Active inflammatory lesions were detected across disease stages and treatments.
Disclosure: G.Datta: nothing to disclose
A.Colasanti: nothing to disclose
N.J. Kalk: nothing to disclose
D.R. Owen: nothing to disclose
G.Scott: nothing to disclose
E.A.Rabiner: holds stock in GSK, has received research funds from AbbVie, and consultancy/speaker fees from GSK, BioTie, Gedeon Richter, Teva and LighlakeTherapeutics
R.N. Gunn: Consultant for GSK, Abbvie, UCB and ITI
A.R. Lingford-Hughes: Research support from GSK
O. Malik: Honoraria and travel bursaries for attendance at conferences from: Biogen Idec, Novartis and Merck/Serono.
O. Ciccarelli: Consultant for Novartis, Biogen and GE
R.Nicholas. Bayer, Biogen, Genzyme, Merck Serono, Roche - honorarium for speaking, advisory boards. Biogen, Genzyme, Novartis - funds for organising education, staff. Biogen, Novartis - Principal investigator.
M. Battaglini: nothing to disclose
N.De Stefano: Honoraria from Schering, Biogen Idec, Teva Pharmaceutical Industries, Novartis, Genzyme, and Merck Serono SA for consulting services, speaking, and travel support. He serves on advisory boards for Biogen Idec, Merck Serono SA, Novartis and Genzyme
This project has been sponsored by Imperial College London, London, UK
Funding has been from GSK and the Wellcome Trust, UK